Potentiation of drug response

ABSTRACT

The power of fluoxetine, venlafaxine, milnacipran and duloxetine to increase the availability of serotonin, norepinephrine and dopamine, particularly serotonin, is augmented by administration in combination with a drug which is a serotonin 1A receptor antagonist.

CROSS-REFERENCE

This application is a division of application Ser. No. 08/277,460, filedJul. 19, 1994, now abandoned, which is a continuation-in-part ofapplication Ser. No. 08/260,857, filed Jun. 16, 1994, now abandoned.

FIELD OF THE INVENTION

The present invention belongs to the fields of pharmacology, medicineand medicinal chemistry, and provides a method and compositions forincreasing the availability of serotonin, norepinephrine and dopamine inthe brain of patients to whom is administered fluoxetine, venlafaxine,milnacipran or duloxetine.

BACKGROUND OF THE INVENTION

Over the past twenty years or more, the science of pharmacology has beenparticularly interested in the physiology of the neurons containingmonoamines in the human brain. Discovery has followed discovery in thefield and it has now been demonstrated that serotonin, norepinephrineand dopamine interact with a great number of receptors in the brain andcontrol or affect processes which regulate many bodily organs andfunctions. Serotonin, particularly, has been found to be the key to alarge number of processes which reveal themselves in both physiologicaland psychological functions.

Perhaps the most dramatic discovery in medicinal chemistry in the recentpast is fluoxetine, a serotonin reuptake inhibitor, which is extremelyeffective in the treatment of depression. As a reuptake inhibitor, itincreases the availability of serotonin in the synapse by reducing theuptake of serotonin by the serotonin uptake carrier. Dysfunction of theserotonin neurons resulting from excessive uptake results in depression,as well as other pathologies of the central nervous system. Not only isfluoxetine spectacularly effective in depression, it is also effectivein treating numerous other conditions.

A next generation drug is duloxetine, which is a reuptake inhibitor ofboth serotonin and norepinephrine. It is now in advanced clinical trialsin the treatment of both depression and urinary incontinence, and is avery effective drug. Venlafaxine and milnacipran are also reuptakeinhibitors of both serotonin and norepinephrine.

While the primary activity of fluoxetine is the inhibition of thereuptake of serotonin, the cascade of monoamine processes in the brainconnects serotonin with both norepinephrine and dopamine. Thus, theincrease of availability of serotonin results in increased availabilityof norepinephrine and dopamine as well. Similarly, the inhibition of theuptake of serotonin and norepinephrine by duloxetine, as well asvenlafaxine and milnacipran, also increases dopamine availability.

The present invention provides a method for increasing the availabilityof serotonin, norepinephrine and dopamine, even compared to the usualincreased availability caused by fluoxetine, venlafaxine, milnacipranand duloxetine, by potentiating the action of those drugs.

SUMMARY OF THE INVENTION

The invention provides a method for potentiating the action of a firstcomponent chosen from the group consisting of fluoxetine, venlafaxine,milnacipran, and duloxetine in increasing the availability of serotonin,norepinephrine and dopamine in the brain, comprising administering afirst component in combination with a second component chosen from thegroup consisting of alprenolol, WAY 100135, spiperone, pindolol,(S)-UH-301, penbutolol, propranolol, tertatolol, and a compound of theformula ##STR1## wherein Ar is ##STR2## R₁ is an optional methyl groupsubstituted on one of the three connecting carbon atoms;

R₂ is hydrogen, C₁ -C₄ alkyl, trifluoromethyl, hydroxy, (C₁ -C₄alkyl)--O--, (C₁ -C₄ alkyl)--S(O)_(p) --, or halo;

R₃ is C₃ -C₈ cycloalkyl or a bicycloalkyl group of the formula ##STR3##where a and c are independently 1-5, b is 0-5, and (a+c) is greater than2;

z is a straight or branched C₄ -C₁₀ alkane, alkene, or alkyne group; (C₄-C₈ cycloalkyl) optionally substituted with C₁ -C₄ alkyl or phenyl; abicycloalkyl group of the formula ##STR4## wherein a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; optionallyphenyl substituted C₂ -C₁₀ alkyl where the phenyl group can beoptionally substituted with R₂ as previously defined; or (C₁ -C₄alkylidene)--T--(C₁ -C₄ alkyl), where T is --O--, --S--, --SO--, or--SO₂ --;

where

each G is independently a bond or C₁ -C₄ alkylidene;

X is --H, --COY, --CN, or C₁ -C₄ alkyl;

Y is --OH, --O--(C₁ -C₄ alkyl), or --NH₂ ;

R_(a) and R_(a') are independently hydrogen or C₁ -C₃ alkyl, or whentaken together with the carbon atom to which they are attached form a C₃-C₈ cycloalkyl ring;

p is 0, 1, or 2;

A is --O--, --S--, --NH--, or --NCH₃ --; and

m is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

The invention also provides pharmaceutical compositions which comprise afirst component in combination with one of the second componentcompounds named above. Further, it provides methods of treating apathological condition which is created by or is dependent upondecreased availability of serotonin, dopamine or norepinephrine, whichcomprise administering to a patient in need of such treatment anadjunctive therapy comprising a first component and one of the compoundsnamed above.

Still further, the invention provides a preferred manner of carrying outthe above method of adjunctive therapy wherein the second component isadministered in a manner which provides a substantially constant bloodlevel of the second component, which level is sufficient to provide asubstantially constant degree of potentiation of the action of the firstcomponent. Compositions adapted for carrying out the preferred manner ofthe invention are also provided.

DESCRIPTION OF PREFERRED EMBODIMENTS

In this document, all temperatures are described in degrees Celsius, andall amounts, ratios of amounts and concentrations are described inweight units unless otherwise stated.

THE COMPOUNDS

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U.S. Pat. No. 4,314,081 is an early reference onthe compound. Robertson et al., J. Med. Chem. 31, 1412 (1988), taughtthe separation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word "fluoxetine" will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word "duloxetine" will be used here to refer toany acid addition salt or the free base of the molecule.

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent.

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moretet al., Neuropharmacology 24, 1211-19 (1985), describe itspharmacological activities.

Duloxetine and fluoxetine, as well as the other first components, areknown to increase the availability of serotonin (5-HT), dopamine (DA)and norepinephrine (NE), and the second component drugs potentiate thatvaluable property. The second component drugs have in common theproperty of being antagonists of the serotonin 1A receptor.

(S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-dipropylaminotetralin) is wellknown to pharmacologists and pharmaceutical chemists. Hillver et al.taught its synthesis in J. Med. Chem. 33, 1541-44 (1990) and Moreau etal., Brain Res. Bull.29, 901-04 (1992) provided considerable in vivodata about the compound.

Alprenolol (1-(1-methylethyl)amino-3-[2-(2-propenyl)phenoxy]-2-propanol)was disclosed by Brandstrom et al., U.S. Pat. No. 3,466,325, which showsits preparation as Example 5.

WAY 100135(N-(t-butyl)-3-[4-{2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide)was disclosed by Abou-Gharbia et al., U.S. Pat. No. 4,988,814, whotaught that the compound has affinity for the 5-HT_(1A) receptor. Cliffeet al., J. Med. Chem. 36, 1509-10 (1993) showed that the compound is a5-HT_(1A) antagonist.

Spiperone(8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one)is a well-known compound, taught in U.S. Pat. Nos. 3,155,669 and3,155,670. Its activity as a 5-HT_(1A) antagonist is shown by Middlemisset al., Neurosci. and Biobehav. Rev. 16, 75-82 (1992).

Tertatolol (8-(3-t-butylamino-2-hydroxypropyloxy)thiochroman) wasdisclosed by Malen et al., U.S. Pat. No. 3,960,891, which teaches it tobe a blocker of cardiac beta-adrenergic receptors. Its other activities,including the presently used 5-HT_(1A) antagonist activity, have beendiscovered since the original patents appeared.

Propranolol (1-isopropylamino-3-(1-naphthalenyloxy)-2-propanol) wasdisclosed by Crowther et al., U.S. Pat. No. 3,337,628 to be abeta-blocker like tertatolol. Again, its other properties are also wellknown to pharmacologists.

Penbutolol (1-(t-butylamino)-2-hydroxy-3-(2-cyclopentyl-phenoxy)propane)was taught by Ruschig et al., U.S. Pat. No. 3,551,493, which describesit as a beta-blocker. Both the (-) and the (+) enantiomers of penbutololare of interest; the (-) enantiomer is preferred for the present purposebut both enantiomers and the racemic mixture are included in the word"penbutolol" in this document.

Pindolol (4-(2-hydroxy-3-isopropylaminopropoxy)indole) was disclosed byTroxler et al., U.S. Pat. No. 3,471,515, which describes this compoundas well as a beta-blocker. The compound is usually administered as theracemic mixture, but the two enantiomers have been isolated and the (-)enantiomer is preferred if a single isomer product is desired in a givenapplication. Both enantiomers and the racemic mixture are included inthe word "pindolol" in this document.

The compounds of formula I are taught by Beedle, et al., U.S. Pat. No.5,013,761, the description of which is incorporated herein by reference.The synthesis and characteristics, including the 5HT_(1A) antagonistactivity, of the compounds is shown in that patent.

The particularly preferred compounds of formula I include, for example,the following individual compounds. It will be understood that thefollowing compounds are typical of those of formula 1 but that thecompounds include numerous other valuable species as shown by thepreviously mentioned U.S. patent. It will be further understood that,while individual salts, and in some cases, enantiomers, are mentionedbelow and are of particular interest, other salts, and enantiomers,diastereomers, and racemates, are likewise valuable and are included informula I as agents for the present invention.

1-(4-indolyloxy)-3-cyclohexylamino-2-propanol, maleate salt;

cis-1-(4-indolyloxy)-3-(4-phenylcyclohexyl-amino)-2-propanol, oxalatesalt;

1-(4-indolyloxy)-3-(2-phenylethylamino)-2-propanol, oxalate salt;

1-(4-indolyloxy)-3-(3-phenylpropylamino)-2-propanol, oxalate salt;

1-(4-indolyloxy)-3-(4-phenylbutylamino)-2-propanol, oxalate salt;

1-(4-indolyloxy)-3-cyclopentylamino-2-propanol, maleate salt;

1-(4-indolyloxy)-3-cycloheptylamino-2-propanol;

(S)-(-)-1-(4-indolyloxy)-3-cyclohexylamino-2-propanol, maleate salt;

(+)-1-(4-indolyloxy)-3-cyclohexylamino-2-propanol, maleate salt;

1-(4-indolyloxy)-3-(3-methylcyclohexylamino)-2-propanol;

1-(4-indolyloxy)-3-(4-methylcyclohexylamino)-2-propanol;

1-(4-indolyloxy)-3-(5-phenylpentylamino)-2-propanol, oxalate salt;

1-(4-indolyloxy)-3-(6-phenylhexylamino)-2-propanol, oxalate salt;

1-(4-indolyloxy)-3-(2,3-dimethylcyclohexyl-amino)-2-propanol, oxalatesalt;

(+-)-1-(4-indolyloxy)-3-(3-pentylamino)-2-propanol;

(R)-(+)-1-(4-indolyloxy)-3-cyclohexylamino-2-propanol, butanedioatesalt;

(R)-(-)-1-(4-indolyloxy)-3-cyclohexylamino-2-propanol, butanedioatesalt;

1-(2-trifluoromethyl-4-benzimidazolyl)-3-(4-phenylbutylamino)-2-propanol;

(exo)-1-(4-indolyloxy)-3-(norbornylamino)-2-propanol;

(endo)-1-(4-indolyloxy)-3-(norbornylamino)-2-propanol;

1-(1-napthalenyloxy)-3-cycloheptylamino-2-propanol, oxalate salt;

1-(2-cyclopentylphenoxy)-3-cycloheptylamino-2-propanol, oxalate salt;

1-(2-cyclohexylphenoxy)-3-cyclooctylamino-2-propanol, oxalate salt;

1-(2-cycloheptylphenoxy)-3-(1,2,3-trimethyl-2-propylamino)-2-propanol,oxalate salt; and

1-(2-cyclopropylphenoxy)-3-(1,1-dimethylbutylamino)-2-propanol, oxalatesalt.

The group of the compounds of formula I wherein the group Ar is indolylor substituted indolyl constitutes a further preferred class of5-HT_(1A) antagonists; and the compounds of formula 1 wherein Z is (C₄-C₈ cycloalkyl) optionally substituted with C₁ -C₄ alkyl or phenyl; or Zrepresents optionally phenyl substituted C₂ -C₁₀ alkyl where the phenylgroup can be optionally substituted with R₂ ; constitute furtherparticularly preferred classes of compounds for use in the presentinvention.

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

While all combinations of first component and second component compoundsare useful and valuable, certain combinations are particularly valuedand are preferred, as follows:

fluoxetine/pindolol

duloxetine/pindolol

fluoxetine/penbutolol

duloxetine/penbutolol

fluoxetine/propranolol

duloxetine/propranolol

fluoxetine/tertatolol

duloxetine/tertatolol

fluoxetine/4-(2-hydroxy-3-cyclohexylaminopropoxy)indole

duloxetine/4-(2-hydroxy-3-cyclohexylaminopropoxy)indole

In general, combinations and methods of treatment using fluoxetine orduloxetine as the first component are preferred.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein, and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

ADMINISTRATION

The dosages of the drugs used in the present invention must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferreddosages, can and will be provided here. Dosage guidelines for some ofthe drugs will first be given separately; in order to create a guidelinefor any desired combination, one would choose the guidelines for each ofthe component drugs.

Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day;

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day;

Pindolol: from about 1 to about 60 mg once-thrice/day; preferred, fromabout 5 to about 60 mg once-thrice/day; also preferred, from about 1 toabout 10 mg twice/day;

Penbutolol: from about 2 to about 80 mg once/day; preferred, from about10 to about 80 mg once/day; also preferred, from about 2 to about 20 mgonce/day;

Propranolol: from about 10 to about 240 mg once-twice/day; preferred,from about 10 to about 120 mg twice/day; also preferred, from about 40to about 240 mg once-twice/day;

4-(2--Hydroxy-3-cyclohexylaminopropoxy)indole: from about 1 to about 50mg once-twice/day; preferred, from about 1 to about 10 mg twice/day.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of first component compound according tothe spirit of the above guideline, and choosing a dosage of the secondcomponent compound in the general range of from about 1 to about 250mg/dose. More preferred dosages, depending on the compound, would befrom about 1 to about 100 mg/dose, and even more preferred dosages wouldbe likely to be found in the range of from about 1 to about 50 mg/dose,ideally from about 1 to about 25 mg/dose.

The adjunctive therapy of the present invention is carried out byadministering a first component together with one of the secondcomponent compounds in any manner which provides effective levels of thetwo compounds in the body at the same time. All of the compoundsconcerned are orally available and are normally administered orally, andso oral administration of the adjunctive combination is preferred. Theymay be administered together, in a single dosage form, or may beadministered separately.

However, oral administration is not the only route or even the onlypreferred route. For example, transdermal administration may be verydesirable for patients who are forgetful or petulant about taking oralmedicine. One of the drugs may be administered by one route, such asoral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

It is particularly preferred, however, for the adjunctive combination tobe administered as a single pharmaceutical composition, and sopharmaceutical compositions incorporating both a first component and asecond component compound are important embodiments of the presentinvention. Such compositions may take any physical form which ispharmaceutically acceptable, but orally usable pharmaceuticalcompositions are particularly preferred. Such adjunctive pharmaceuticalcompositions contain an effective amount of each of the compounds, whicheffective amount is related to the daily dose of the compounds to beadministered. Each adjunctive dosage unit may contain the daily doses ofboth compounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug Lo be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

The second component compounds, taken as a class, have short lives inthe body and, accordingly, provide only short periods of activityfollowing each dose. For example, pindolol is routinely administeredtwice/day in the prior art, and it has been administered even moreoften. In the context of the present invention, it is thereforepreferred to administer the second component compounds in a manner whichsupplies a substantially constant blood level of the second component inthe body of the patient, at a sufficiently high level to provide asubstantially constant degree of potentiation of the action of the firstcomponent.

It is not intended, of course, that the present invention or any methodof human treatment can provide a truly constant blood level and degreeof potentiation. Biological processes always vary and prevent preciselyconstant results. The term "substantially constant" is used herein torefer to administration resulting in blood levels and degrees ofpotentiation which are sufficiently constant as to provide continuousimproved efficacy over a treatment day, compared to the efficacy of thefirst component compound alone. Another way to consider substantiallyconstant potentiation is by comparing the availability of serotonin,norepinephrine and dopamine in the brain of the patient. By"substantially constant" in such terms is meant a condition where thepeak and the valley of availability differ by no more than about afactor of 2 over the course of a treatment day. Another way to consider"substantially constant" is a condition where the peak and valley differby no more than about a factor of 1.5; or they differ by no more than arange of from about 1.5 to about 3.

Such administration of the second component may be provided by meansknown to pharmaceutical scientists. For example, the total daily dosageof a second component may be formulated in a manner which provides asubstantially constant flow of compound to the patient. To consider onlypindolol, at least the following references teach sustained releaseformulations: German Patent 3632201, capsules; Swiss Patent 634990,tablets; German Patent 3237945, buccal tape; German Patent 2732335,tablets; U.S. Pat. No. 5,260,066, cryogels; European Patent Publication361894, liposomes; Japanese Patent 84-66710, transdermal patches.Pharmaceutical scientists are acquainted in modern practice with themanners of adjusting a sustained release formulation to provide thedesired rate of administration of a given compound and such formulationscan be prepared by the skill of the pharmaceutical art of the compoundsused as second components here.

Such formulations of a second component compound may be combined in asingle dosage form with the chosen first component compound. Forexample, a small tablet or pellets of the second component, formulatedto provide constant availability of the compound, may be combined, forexample in a capsule, with the first component compound. Alternatively,a transdermal patch may be prepared which has a relatively rapidlyreleasing area of first component, and a relatively slowly releasingarea of second component. Still further, a suspension may be prepared inwhich the first component is present as particles of pure compound, andthe particles of the second component are coated to provide sustainedrelease in the body. In such manners, the availability of the secondcomponent may be adjusted to provide the desired substantially constantblood levels and, hence, substantially constant potentiation of thefirst component. Compositions so adapted for providing substantiallyconstant potention of the first component are preferred compositions ofthe present invention.

The inert ingredients and manner of formulation of the adjunctivepharmaceutical compositions are conventional, except for the presence ofthe combination of the first component and the second componentcompound. The usual methods of formulation used in pharmaceuticalscience may be used here. All of the usual types of compositions may beused, including tablets, chewable tablets, capsules, solutions,parenteral solutions, intranasal sprays or powders, troches,suppositories, transdermal patches and suspensions. In general,compositions contain from about 0.5% to about 50% of the compounds intotal, depending on the desired doses and the type of composition to beused. The amount of the compounds, however, is best defined as theeffective amount, that is, the amount of each compound which providesthe desired dose to the patient in need of such treatment. The activityof the adjunctive combinations do not depend on the nature of thecomposition, so the compositions are chosen and formulated solely forconvenience and economy. Any of the combinations may be formulated inany desired form of composition. Some discussion of differentcompositions will be provided, followed by some typical formulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acid contents of the stomach. Such formulations are createdby coating a solid dosage form with a film of a polymer which isinsoluble in acid environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate. It is preferred to formulateduloxetine and duloxetine-containing combinations as entericcompositions, and even more preferred to formulate them as entericpellets.

A preferred duloxetine enteric formulation is a pellet formulationcomprising a) a core consisting of duloxetine and a pharmaceuticallyacceptable excipient; b) an optional separating layer; c) an entericlayer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS)and a pharmaceutically acceptable excipient; d) an optional finishinglayer. The following example demonstrates the preparation of a preferredsuch formulation.

EXAMPLE

    ______________________________________                                        10 mg Duloxetine base/capsule                                                 Bill of Materials                                                             ______________________________________                                        Beads                                                                         Sucrose - starch nonpareils,                                                  20-25 mesh                60.28   mg                                          Duloxetine layer                                                              Duloxetine                11.21                                               Hydroxypropylmethylcellulose                                                                            3.74                                                Separating layer                                                              Hydroxypropylmethylcellulose                                                                            2.51                                                Sucrose                   5.00                                                Talc, 500 mesh            10.03                                               Enteric layer                                                                 HPMCAS, LF grade, Shin-Etsu Chemical                                                                    25.05                                               Co., Tokyo, Japan                                                             Triethyl citrate          5.00                                                Talc, 500 mesh            7.52                                                Finishing layer                                                               Hydroxypropylmethylcellulose                                                                            8.44                                                Titanium dioxide          2.81                                                Talc                      Trace                                                                         141.60  mg                                          ______________________________________                                    

The duloxetine layer was built up by suspending deloxetine in a 4% w/wsolution of the hydroxypropylmethylcellulose in water, and milling thesuspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden,Switzerland) model MS-12. A fluid bed dryer with a Wurster column wasused to make this product, at a batch size of 1.0 kg. The separatinglayer was added from a 4% w/w solution of thehydroxypropylmethylcellulose in water, in which the sucrose was alsodissolved.

In order to prepare the enteric coating suspension, purified water wascooled to 10° C. and the polysorbate, triethyl citrate and siliconeemulsion were added and dispersed or dissolved. Then the HPMCAS and talcwere added and agitated until homogeneity was obtained, and the HPMCASwas fully neutralized by addition of ammonium hydroxide until solutionof the polymer was complete. To this suspension, acarboxymethylcellulose aqueous solution, 0.5% w/w, was added and blendedthoroughly. The enteric suspension was maintained at 20° C. during thecoating process. The enteric suspension was then added to the partiallycompleted pellets in the Wurster column at a spray rate of about 15ml/min, holding the temperature of the inlet air at about 50° C. Theproduct was dried in the Wurster at 50° C. when the enteric suspensionhad been fully added, and then dried on trays for 3 hours in a dry houseat 60° C. A finishing layer was then applied which consisted of a 4.5%w/w/hydroxypropylmethylcellulose solution containing titanium dioxideand propylene glycol as plasticizer. The pellets were completely driedin the fluid bed dryer and then were then filled in size 3 gelatincapsules.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the patient consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some patients.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                            Quantity                                                                      (mg/capsule)                                              ______________________________________                                        Fluoxetine, racemic, hydrochloride                                                                  20        mg                                            Pindolol              30                                                      Starch, dried         200                                                     magnesium stearate    10                                                      Total                 260       mg                                            ______________________________________                                    

FORMULATION 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                            Quantity                                                                      (mq/capsule)                                              ______________________________________                                        Fluoxetine, racemic, hydrochloride                                                                  10                                                      (-)-Penbutolol        40                                                      Cellulose, microcrystalline                                                                         400                                                     Silicon dioxide, fumed                                                                              10                                                      Stearic acid          5                                                       Total                 465       mg                                            ______________________________________                                    

The components are blended and compressed to form tablets each weighing465 mg.

FORMULATION 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                            Weight                                                    ______________________________________                                        (+)-Duloxetine, hydrochloride                                                                       10                                                      Pindolol              10                                                      Ethanol               25.75                                                   Propellant 22         70.00                                                   (Chlorodifluoromethane)                                                       Total                 115.75                                                  ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

FORMULATION 4

Tablets, each containing 80 mg of active ingredient, are made asfollows:

    ______________________________________                                        (+)-Duloxetine, hydrochloride                                                                          20     mg                                            (-)-Penbutolol           60     mg                                            Starch                   45     mg                                            Microcrystalline cellulose                                                                             35     mg                                            Polyvinylpyrrolidone     4      mg                                            (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                            4.5    mg                                            Magnesium stearate       0.5    mg                                            Talc                     1      mg                                            Total                    170    mg                                            ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl- pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 170 mg.

FORMULATION 5

Capsules, each containing 130 mg of active ingredient, are made asfollows:

    ______________________________________                                        Fluoxetine, racemic, hydrochloride                                                                     30     mg                                            Propranolol              100    mg                                            Starch                   59     mg                                            Microcrystalline cellulose                                                                             59     mg                                            Magnesium stearate       2      mg                                            Total                    250    mg                                            ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 250 mg quantities.

FORMULATION 6

Suppositories, each containing 45 mg of active ingredient, are made asfollows:

    ______________________________________                                        (+)-Duloxetine, hydrochloride                                                                          5      mg                                            Propranolol              40     mg                                            Saturated fatty acid glycerides                                                                        2,000  mg                                            Total                    2,045  mg                                            ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 7

Suspensions, each containing 70 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        Fluoxetine, racemic, hydrochloride                                                                     10     mg                                            Propranolol              60     mg                                            Sodium carboxymethyl cellulose                                                                         50     mg                                            Syrup                    1.25   ml                                            Benzoic acid solution    0.10   ml                                            Flavor                   q.v.                                                 Color                    q.v.                                                 Purified water to total  5      ml                                            ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        (+)-Duloxetine, hydrochloride                                                                          10     mg                                            Propranolol              20     mg                                            Isotonic saline          1,000  ml                                            ______________________________________                                    

BENEFIT OF THE INVENTION

As stated above, the benefit of the invention is its ability to augmentthe increase in availability of serotonin, norepinephrine and dopaminecaused by the first component compounds, resulting in improved activityin treating the various conditions described below in detail. Theincrease in availability of serotonin is particularly important and is apreferred aspect of the invention. Further, the invention provides amore rapid onset of action than is usually provided by treatment withfluoxetine or duloxetine alone. The experimental data shown belowclearly demonstrate the rapid onset of action, as well as theaugmentation of availability of the monoamines.

Preferred pathological conditions to be treated by the present method ofadjunctive therapy include depression, obsessive-compulsive disease andobesity. Another preferred condition more specific to combinationsincluding preferably duloxetine but also venlafaxine and milnacipran isurinary incontinence.

Depression in its many variations has recently become much more visibleto the general public than it has previously been. It is now recognizedas an extremely damaging disorder, and one that afflicts a surprisinglylarge fraction of the population. Suicide is the most extreme symptom ofdepression, but millions of people, not quite so drastically afflicted,live in misery and partial or complete uselessness, and afflict theirfamilies as well by their affliction. The introduction of fluoxetine wasa breakthrough in the treatment of depression, and depressives are nowmuch more likely to be diagnosed and treated than they were only adecade ago. Duloxetine is in clinical trials for the treatment ofdepression and is likely to become a marketed drug for the purpose.

Depression is often associated with other diseases and conditions, orcaused by such other conditions. For example, it is associated withParkinson's disease; with HIV; with Alzheimer's disease; and with abuseof anabolic steroids. Depression may also be associated with abuse ofany substance, or may be associated with behavioral problems resultingfrom or occurring in combination with head injuries, mental retardationor stroke. Depression in all its variations is a preferred target oftreatment with the present adjunctive therapy method and compositions.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the patient's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted patient may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the U.S. and other countries for the treatmentof obsessive-compulsive disease and has been found to be effective.

Obesity is a frequent condition in the American population. It has beenfound that fluoxetine will enable an obese patient to lose weight, withthe resulting benefit to the patient's circulation and heart condition,as well as general well being and energy.

Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles. Duloxetine controls both types of incontinence, or bothtypes at once, and so is important to the many people who suffer fromthis embarrassing and disabling disorder.

The present invention is useful for treating many other diseases,disorders and conditions as well, as set out below. In many cases, thediseases to be mentioned here are classified in the InternationalClassification of Diseases, 9th Edition (ICD), or in the Diagnostic andStatistical Manual of Mental Disorders, 3rd Version Revised, publishedby the American Psychiatric Association (DSM). In such cases, the ICD orDSM code numbers are supplied below for the convenience of the reader.

depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82, 293.83,310.10, 318.00, 317.00

migraine

pain, particularly neuropathic pain

bulimia, ICD 307.51, DSM 307.51

premenstrual syndrome or late luteal phase syndrome, DSM 307.90

alcoholism, ICD 305.0, DSM 305.00 & 303.90

tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

panic disorder, ICD 300.01, DSM 300.01 & 300.21

anxiety, ICD 300.02, DSM 300.00

post-traumatic syndrome, DSM 309.89

memory loss, DSM 294.00

dementia of aging, ICD 290

social phobia, ICD 300.23, DSM 300.23

attention deficit hyperactivity disorder, ICD 314.0

disruptive behavior disorders, ICD 312

impulse control disorders, ICD 312, DSM 312.39 & 312.34

borderline personality disorder, ICD 301.83, DSM 301.83

chronic fatigue syndrome

premature ejaculation, DSM 302.75

erectile difficulty, DSM 302.72

anorexia nervosa, ICD 307.1, DSM 307.10

disorders of sleep, ICD 307.4

autism

mutism

trichotillomania

EXPERIMENTAL RESULTS

Representative combinations of the present invention have been tested inconscious experimental animals and the surprising results of the testingdemonstrate the benefit of the invention. The tests were carried out asfollows.

MICRODIALYSIS ASSAYS OF MONOAMINES

Sprague-Dawley rats (Harlan or Charles River) weighing 270-300 gramswere surgically implanted with microdialysis probes under chloralhydrate/pentobarbital anesthesia (170 and 36 mg/kg i.p. in 30% propyleneglycol, ethanol) (Perry and Fuller, Effect of fluoxetine on serotoninand dopamine concentration in rat hypothalamus after administration offluoxetine plus L-5-hydroxytryptophan, Life Sci., 50, 1683-90 (1992)). ADavid Kopf stereotaxic instrument was used to implant the probeunilaterally in the hypothalamus at coordinates rostral -1.5 mm, lateral-1.3 mm, and ventral -9.0 mm (Paxinos and Watson, 1986). After a 48 hourrecovery period, rats were placed in a large plastic bowl with a mountedliquid swivel system (CMA/120 system for freely moving animals,Bioanalytical Systems, West Lafayette, Ind.). Filtered artificialcerebrospinal fluid (CSF) (150 mM NaCl, 3.0 mM KCl, 1.7 mM CaCl2, and0.9 mM MgCl2) was perfused through the probe at a rate of 1.0 μl/min.The output dialysate line was fitted to a tenport HPLC valve with a 20μl loop. At the end of each 30 minute sampling period, dialysatecollected in the loop was injected on an analytical column (Spherisorb3μ ODS2, 2×150 mm, Keystone Scientific).

The method used to measure monoamines was as described by Perry andFuller (1993). Briefly, dialysate collected in the 20 μl loop wasassayed for 5-HT, NE and DA. The 20 μl injection went onto the columnwith a mobile phase which resolved NE, DA, and 5-HT: 75 mM potassiumacetate, 0.5 mM ethylenediaminetetraacetic acid, 1.4 mM sodiumoctanesulfonic acid and 8% methanol, pH 4.9. The mobile phase for theamine column was delivered with a flow programmable pump at an initialflow rate of 0.2 ml/min increasing to 0.3 ml/min at 5 min thendecreasing back to 0.2 ml/min at 26 min with a total run time of 30 min.Flow programming was used to elute the 5-HT within a 25 min time period.The electrochemical detector (EG&G, Model 400) for the amine column wasset at a potential of 400 mV and a sensitivity of 0.2 nA/V. The data wascollected and analyzed with a Hewlett-Packard HP1000 chromatographysystem which measured peak heights and calculated sample concentrations.Basal levels were measured for at least 90 minutes prior to drugadministration. The drugs were prepared in filtered deionized water andadministered (volume 0.25-0.3 ml) at the doses stated in the resultsbelow.

EVALUATION AND STATISTICAL ANALYSES

Extracellular levels of the amines in microdialysates were calculated bycomparing peak heights with those of 50 pmole standards. The mean valueof the four samples immediately preceding drug administration served asthe basal level for each experiment and data was converted to percent ofbasal. Paired t-tests were used to compare the mean of the basal valuesfrom the time point immediately preceding drug administration to thoseof each time point thereafter.

The data has been rounded to make the trends more visible.

TEST 1

In this test, the combination therapy comprised fluoxetine as thehydrochloride of the racemate and4-(2-hydroxy-3-cyclohexylaminopropoxy)indole, maleate. The rats wereprepared as described above, and the indole was administeredsubcutaneously at 3 mg/kg 100 minutes after the start of the experiment.Fluoxetine was administered intraperitoneally at 10 mg/kg, together witha second dose of the indole at 3 mg/kg, 210 minutes after the start ofthe experiment. Each data point reported here represents a singleanimal.

The 5-HT level measured in the dialysate declined upon administration ofthe indole, as low as about 50% of baseline, and was at about 80% ofbaseline at 210 minutes. It increased sharply upon administration offluoxetine and was measured at about 410% of baseline at 240 minutes,about 450% of baseline at 270 and about 460% at 300 minutes, and atabout 390% of baseline at 330 minutes.

The NE level increased upon administration of the indole, as high asabout 180% of baseline, and declined nearly to baseline by 210 minutes.Upon administration of fluoxetine, it increased to about 500% ofbaseline at 240 minutes, and declined to about 340%, 280% and 200% ofbaseline at 270, 300 and 330 minutes respectively.

Similarly, DA level increased to about 210% of baseline at 120 minutesand declined to near baseline at 210 minutes. Administration offluoxetine increased the DA level to about 1430% of baseline at 240minutes, about 840% of baseline at 270 minutes, about 530% at 300minutes, and about 330% at 330 minutes.

TEST 2

In this test, the drugs were (+)-duloxetine, hydrochloride, administeredat 4 mg/kg, and (-)-pindolol, at 5 mg/kg. The test was carried out inthe same manner as Test 1, administering the (-)-pindolol first at 120minutes after start of experiment, and then the duloxetine together witha second dose of (-)-pindolol at 5 mg/kg at 210 minutes. The results areshown below as percent of baseline of the three monoamines, at varioustimes after the start of the experiment. Each data point represents theaverage of three or more animals.

    ______________________________________                                        Time          5-HT      NE         DA                                         ______________________________________                                        120 min.      80%       90%        90%                                        150           90        100        90                                         180           110       120        70                                         210           100       110        100                                        240           240       350        230                                        270           340       230        170                                        300           360       210        140                                        330           --        230        150                                        360           330       170        150                                        ______________________________________                                    

TEST 3

This test was carried out as described in Test 1, using4-(2-hydroxy-3-cyclohexylaminopropoxy)indole, maleate, at 3 mg/kgadministered at 120 minutes, and (+)-duloxetine, hydrochloride, at 4mg/kg administered with a second dose of the indole at 3 mg/kg, at 270minutes. Results are reported as in Test 2 above. The 5-HT results arethe average of three animals, and the other results are the average offour animals.

    ______________________________________                                        Time         5-HT       NE         DA                                         ______________________________________                                        120 min.     90%        100%       70%                                        150          130        160        150                                        180          130        140        130                                        210          80         140        110                                        240          90         130        100                                        270          80         150        110                                        300          650        580        410                                        330          670        390        280                                        360          590        450        240                                        390          490        320        210                                        420          440        290        200                                        ______________________________________                                    

We claim:
 1. A method for potentiating the action of a first componentwhich is fluoxetine, in increasing the availability of serotonin,norepinephrine and dopamine in the brain, comprising administeringfluoxetine to a patient in need thereof in combination with a secondcomponent which is a compound of the formula ##STR5## wherein Ar is##STR6## R₁ is an optional methyl group substituted on one of the threeconnecting carbon atoms;R₂ is hydrogen, C₁ -C₄ alkyl, trifluoromethyl,hydroxy, (C₁ -C₄ alkyl)--O--, (C₁ -C₄ alkyl)--S(O)_(p) --, or halo; R₃is a bicycloalkyl group of the formula ##STR7## where a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; z is astraight or branched C₄ -C₁₀ alkane, alkene, or alkyne group; (C₄ -C₈cycloalkyl) optionally substituted with C₁ -C₄ alkyl or phenyl; abicycloalkyl group of the formula ##STR8## wherein a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; optionallyphenyl substituted C₂ -C₁₀ alkyl where the phenyl group can beoptionally substituted with R₂ as previously defined; or (C₁ -C₄alkylidene)--T--(C₁ -C₄ alkyl), where T is --O--, --S--, --SO--, or--SO₂ --;where each G is independently a bond or C₁ -C₄ alkylidene; X is--H, --COY, --CN, or C₁ -C₄ alkyl; Y is --OH, --O--(C₁ -C₄ alkyl), or--NH₂ ; R_(a) and R_(a') are independently hydrogen or C₁ -C₃ alkyl, orwhen taken together with the carbon atom to which they are attached forma C₃ -C₈ cycloalkyl ring; p is 0, 1, or 2; A is --O--, --S--, --NH--, or--NCH₃ --; and m is 0, 1, 2, or 3; or a pharmaceutically acceptable saltthereof.
 2. A method of claim 1 wherein the second component is4-(2-hydroxy-3cyclohexylaminopropoxy)indole.
 3. A method of claim 1wherein the availability of serotonin is increased.
 4. A method of claim1 wherein the second component is administered in a manner whichprovides a substantially constant blood level of the second component,which level is sufficient to provide a substantially constant degree ofpotentiation of the action of the first component.
 5. A method of claim4 wherein the second component is4-(2-hydroxy-3-cyclohexylaminopropoxy)indole.
 6. A method of treating apathological condition which is created by or is dependent upondecreased availability of serotonin, norepinephrine or dopamine, whichcomprises administering to a patient in need of such treatment a firstcomponent which is fluoxetine, in combination with a second componentwhich is a compound of the formula ##STR9## wherein Ar is ##STR10## R₁is an optional methyl group substituted on one of the three connectingcarbon atoms;R₂ is hydrogen, C₁ -C₄ alkyl, trifluoromethyl, hydroxy, (C₁-C₄ alkyl)--O--, (C₁ -C₄ alkyl)--S(O)_(p) --, or halo; R₃ is abicycloalkyl group of the formula ##STR11## where a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; Z is astraight or branched C₄ -C₁₀ alkane, alkene, or alkyne group; (C₄ -C₈cycloalkyl) optionally substituted with C₁ -C₄ alkyl or phenyl; abicycloalkyl group of the formula ##STR12## wherein a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; optionallyphenyl substituted C₂ -C₁₀ alkyl where the phenyl group can beoptionally substituted with R₂ as previously defined; or (C₁ -C₄alkylidene)--T--(C₁ -C₄ alkyl), where T is --O--, --S--, --SO--, or--SO₂ --;where each G is independently a bond or C₁ -C₄ alkylidene; X is--H, --COY, --CN, or C₁ -C₄ alkyl; Y is --OH, --O--(C₁ -C₄ alkyl), or--NH₂ ; R_(a) and R_(a') are independently hydrogen or C₁ -C₃ alkyl, orwhen taken together with the carbon atom to which they are attached forma C₃ -C₈ cycloalkyl ring; p is 0, 1, or 2; A is --O--, --S--, --NH--, or--NCH₃ --; and m is 0, 1, 2, or 3; or a pharmaceutically acceptable saltthereof.
 7. A method of claim 6 wherein the second component is4-(2-hydroxy-3-cyclohexylaminopropoxy)indole.
 8. A method of claim 6wherein the pathological condition ms depression.
 9. A method of claim 6wherein the pathological condition is obsessive-compulsive disease. 10.A method of claim 6 wherein the pathological condition is obesity.
 11. Amethod of claim 6 wherein the pathological condition is late lutealphase syndrome.
 12. A pharmaceutical composition which comprises a firstcomponent which is fluoxetine, in combination with a second componentwhich is a compound of the formula ##STR13## wherein Ar is ##STR14## R₁is an optional methyl group substituted on one of the three connectingcarbon atoms;R₂ is hydrogen, C₁ -C₄ alkyl, trifluoromethyl, hydroxy, (C₁-C₄ alkyl)--O--, (C₁ -C₄ alkyl)--S(O)_(p) --, or halo; R₃ is abicycloalkyl group of the formula ##STR15## where a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; Z is astraight or branched C₄ -C₁₀ alkane, alkene, or alkyne group; (C₄ -C₈cycloalkyl) optionally substituted with C₁ -C₄ alkyl or phenyl; abicycloalkyl group of the formula ##STR16## wherein a and c areindependently 1-5, b is 0-5, and (a+c) is greater than 2; optionallyphenyl substituted C₂ -C₁₀ alkyl where the phenyl group can beoptionally substituted with R₂ as previously defined; or (C₁ -C₄alkylidene)--T--(C₁ -C₄ alkyl), where T is --O--, --S--, --SO--, or--SO₂ --;where each G is independently a bond or C₁ -C₄ alkylidene; X is--H, --COY, --CN, or C₁ -C₄ alkyl; Y is --OH, --O--(C₁ -C₄ alkyl), or--NH₂ ; R_(a) and R_(a') are independently hydrogen or C₁ -C₃ alkyl, orwhen taken together with the carbon atom to which they are attached forma C₃ -C₈ cycloalkyl ring; p is 0, 1, or 2; A is --O--, --S--, --NH--, or--NCH₃ --; and m is 0, 1, 2, or 3; or a pharmaceutically acceptable saltthereof.
 13. A composition of claim 12 wherein the second component is4-(2-hydroxy-3cyclohexylaminopropoxy)indole.
 14. A composition of claim12 which provides a substantially constant blood level of the secondcomponent, which level is sufficient to provide a substantially constantdegree of potentiation of the action of the first component.
 15. Acomposition of claim 14 wherein the second component is4-(2-hydroxy-3-cyclohexylaminopropoxy)indole.